This invention relates to a synthetic quinolone antibacterial agent useful as a drug for humans, animals or fishes or an antibacterial preservative.
This invention also relates to a synthetic quinolone antibacterial agent in which the structure of substituent at the 7 position of 1,4-dihydro-4-oxoquinoline skeleton or at the 10-position of 2,3-dihydro-7-oxo-7H-pyrido[1,2,3-de][1.4]benzoxazine skeleton exerts important influence upon the expression of pharmacological effects such as antibacterial activity, pharmacokinetics and safety, having a 3-[1-amino-1-cycloalkyl]methylpyrrolidin-1-yl group which can provide excellent antibacterial activity, pharmacokinetics and safety, as a substituent at the 7- or 10-position, and also having excellent antibacterial activity, proper pharmacokinetics and high safety, namely to a 6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid derivative or a 2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de][1.4]benzoxazine-6-carboxylic acid derivative, and to an antibacterial agent and an antibacterial preparation, which contain the compound.
Since the discovery of Norfloxacin, antibacterial activity and pharmacokinetics of synthetic quinolone antibacterial agents have been improved, and many compounds are now used in the clinical field as chemotherapeutic agents which are effective in almost systemic infectious diseases.
In recent years, generation of bacteria having low sensitivity to synthetic quinolone antibacterial agents has been increasing in the field of clinics. For example, like the case of Staphylococcus aureus (MRSA) and pneumococcus (PRSP) which are non-sensitive to xcex2-lactam antibiotics and enterococcus (VRE) which is non-sensitive to aminoglycoside antibacterial agents, a case has been increasing in which a Gram-positive bacterium originally resistant to drugs other than synthetic quinolone antibacterial agents becomes low-sensitive to synthetic quinolone antibacterial agents too. In consequence, development of a drug having further high efficacy has been called for in the field of clinics. On the other hand, it has been revealed that synthetic quinolone antibacterial agents cause a side effect in which convulsion is induced when a non-steroidal anti-inflammatory drug is simultaneously used, as well as other side effects such as phototoxicity, so that development of a synthetic quinolone antibacterial agent having further high safety has also been called for in the field.
It is known that structures of substituents at the 7-position and 1-position have a great influence to the antibacterial activity, pharmcokinetics and safety of synthetic quinolone antibacterial agents. It is already known that quinolone derivatives having 3-aminamethylpyrrolidine as a substituent show strong antibacterial activity for Gram-negative and Gram-positive bacteria. For example, a 7-(3-ainomethylpyrrolidin-1-yl)quinolonecarboxylic acid derivative is described in Journal of Medicinal Chemistry, vol. 29, p. 445 (1986), a 7-[3-(1-amino-1-methylethyl)pyrrolidin-1-yl)quinolonecarboxylic acid derivative is described in Journal of Medicinal Chemistry, vol. 37, p. 733 (1994), and a 7-[3-(1-aminoalkyl)pyrrolidin-1-yl]quinolonecarboxylic acid derivative is described in Chemicaland Pharmaceutical Bulletin, vol. 42, p. 1442 (1994). However, no compounds are known which have a 3-(1-amino-1-cycloalkyl)methylpyridin-1-yl group at the 7-position and are also related to the present invention.
On the other hand, quinolone derivatives having 3-aminomethylpyrrolidine as a substituent are compounds which show strong antibacterial activity, but, since most of these compounds have low selective toxicity, they act upon not only bacteria but also eucaryotic cells so that it is difficult to use them as medical drugs or animal drugs.
Also, it is known that quinolone derivatives having a 3-aminopyrrolidine derivative at the 7-position and 2-(S)-fluoro-1-(R)-cyclopropyl group at the 1-position of the quinoline skeleton have weaker micronucleus inducing toxicity than those corresponding 1-cyclopropylquinolone derivatives. Their examples are described in Journal of Medicinal Chemistry, vol. 37. P. 3344 (1994).
On the other hand, quinolonecarboxylic acid derivatives having a 3-[1-amino-1-cycloalkyl]methylpyrrolidin-1-yl group as a substituent, which are related to the present invention, are exemplified for example in JP-W-3-502452 (the term xe2x80x9cJP-Wxe2x80x9d as used herein means an xe2x80x9cunexamined published Japanese international patent applicationxe2x80x9d), and it describes compounds represented by a formula (a) or (b) shown below. However, substituent at the 5-position of these exemplified quinolones is limited to a straight, branched or cyclic lower alkyl having 1 to 3 carbon atoms, and JP-W-3-502452 does not describe compounds having the 1-[2-(S)-fluoro-1-(R)-cyclopropyl]quinoline skeleton or 3-(S)-methyl-7H-pyrido[1,2,3-de][1.4]benzoxazine skeleton related to the present invention. In addition, JP-W-3-502452 does not disclose illustrative examples of the 3-[1-amino-1-cycloalkyl]methylpyrrolidin-1-yl group. 
[In the above formula, R7 is an alkyl having 1 to 4 carbon atoms, a vinyl, a haloalkyl, a hydroxyalkyl having 2 to 4 carbon atoms, a cycloalkyl having 3 to 6 carbon atoms, a phenyl or a phenyl substituted with a halogen, an alkyl, NH2 or OH, R6 is a straight, branched or cyclic lower alkyl having 1 to 3 carbon atoms, and X3 is CH, CF, CCl, CBr, N, CCF3, CNH2, CNO2, CR or CORxe2x80x2 (in these formulae, R is a lower alkyl and Rxe2x80x2 is hydrogen or a lower alkyl). Definitions of substituents of the compound of formula (a) are independent to those the compound of the present invention.]
In the above formula, Z is a group represented by the following formula (b). 
(In this formula, m is an integer of from 0 to 4, and the substituents R9 and R10 are each independently a hydrogen atom, a lower alkyl or a cycloalkyl. Definitions of substituents of the compound of formula (b) are independent to those the compound of the present invention.)
In addition, PCT WO 96/39407 discloses compounds represented by the following formula (c), but they are limited to 2-pyridone derivatives such as 4H-4-oxoquinotozone skeleton, and PCT WO 96/39407 does not describe compounds having the 1,4-dihydro-4-oxoquinoline skeleton or 2,3-dihydro-3-(S)-ethyl-7-oxo-7H-pyrido[1,2,3-de][1.4]benzoxazine skeleton related to the present invention. Also, PCT WO 96/39407 does not disclose illustrative examples of optically active 3-[1-amino-1-cyclopropyl]methylpyrrolidin-1-yl group.
In addition, PCT WO 96/39407 does not describe about safety of the compounds of formula (c). 
In view of the above, the inventors of the present invention have conducted intensive studies with the aim of providing the field of clinics with a compound which has excellent antibacterial activity, high efficacy and excellent safety. As a result of the extensive investigation, it has been found absolutely unexpectedly that a cycloalkyl-substituted aminomethylpyrrolidine derivative represented by the formula (I) described below, its salts and hydrates thereof can show strong antibacterial activity upon broad range of Gram-negative and Gram-positive bacteria, can show particularly strong antibacterial activity upon resistant strains of Gram-positive bacteria including MRSA, PRSP and VRE, and also have excellent safety and good pharmacokinetics, thereby resulting in the accomplishment of the present invention.
Particularly, it has been found that a compound represented by the following formula (I) in which a cycloalkyl-substituted aminomethylpyrrolidine derivative is introduced at the 7position of the 1[2-(S)-fluoro-1-(R)-cyclopropyl]quinoline skeleton, its salts and hydrates thereof show broad and excellent antibacterial activity upon any one of Gram-negative and Gram-positive bacteria including drug-resistant strains, have excellent safety with sharply attenuated micronucleus induction action, and also have excellent pharmacokinetics.
Accordingly, the present invention relates to a compound represented by the following formula (I), its salts and hydrates thereof: 
{wherein R1 and R2 each independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, in which the alkyl group may have one or more substituents selected from the group consisting of a hydroxyl group, a halogen atom, an alkylthio group having 1 to 6 carbon atoms and an alkyloxy group; n is an integer of 1 to 4; and Q is a partial structure represented by the following formula (Ia): 
[wherein R3 represents an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, a halogenoalkyl group having 1 to 6 carbon atoms, a cyclic alkyl group having 3 to 6 carbon atoms which may have a substituent, an aryl group which may have a substituent, a heteroaryl group which may have a substituent, an alkoxyl group having 1 to 6 carbon atoms or an alkylamino group having 1 to 6 carbon atoms;
R4 represents a hydrogen atom or an alkylthio group having 1 to 6 carbon atoms;
R4 and the aforementioned R3 may form together with a part of the mother skeleton a ring structure optionally containing a sulfur atom as a ring constituting atom thereof and optionally having an alkyl group having 1 to 6 carbon atoms as a substituent;
R5 represents a hydrogen atom, an amino group, a hydroxyl group, a thiol group, a halogenomethyl group, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms or an alkoxyl group having 1 to 6 carbon atoms, in which the amino group may have one or more substituents selected from the group consisting of formyl group, an alkyl group having 1 to 6 carbon atoms and an acyl group having 2 to 5 carbon atoms;
X1 represents a halogen atom or a hydrogen atom,
A1 represents a nitrogen atom or a partial structure represented by formula (II): 
(wherein x2 represents a hydrogen atom, an amino group, a halogen atom, a cyano group, a halogenomethyl group, a halogenamethoxyl group, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms or an alkoxyl group having 1 to 6 carbon atoms, in which the amino group may have one or more substituents selected from the group consisting of a formyl group, an alkyl group having 1 to 6 carbon atoms and an acyl group having 2 to 5 carbon atoms; and
X2 and the aforementioned R3 may form together with a part of the mother skeleton a ring structure optionally containing an oxygen atom, a nitrogen atom or a sulfur atom as a ring constituting atom thereof and optionally having an alkyl group having 1 to 6 carbon atoms as a substituent); and
Y represents a hydrogen atom, a phenyl group, an acetoxymethyl group, a pivaloyloxymethyl group, an ethoxycarbonyl group, a choline group, a dimethylaminoethyl group, a 5-indanyl group, a phthalidinyl group, a 5-alkyl-2-oxo-1,3-dioxol-4-ylmethyl group, a 3-acetoxy-2-oxobutyl group, an alkyl group having 1 to 6 carbon atoms, an alkoxymethyl group having 2 to 7 carbon atoms or a phenylalkyl group composed of an alkylene group having 1 to 6 carbon atoms and a phenyl group]}.
The present invention also relates to each of the following items.
A compound, its salts and hydrates thereof, wherein Q in the formula (I) is a 6-caxboxy-9-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de][1.4]benzoxazin-10-yl group;
the aforementioned compound, its salts and hydrates thereof, wherein the compound of formula (I) is a stereochemically pure compound;
the aforementioned compound, its salts and hydrates thereof, wherein R3 in the formula (I) is a halogenocyclopropyl group;
the aforementioned compound, its salts and hydrates thereof, wherein the halogenocyclopropyl group in the formula (I) is a 1,2-cis-halogenocyclopropyl group;
the aforementioned compound, its salts and hydrates thereof, wherein the halogenocyclopropyl group in the formula (I) is a stereochemically pure substituent;
the aforementioned compound, its salts and hydrates thereof, wherein the halogenocyclopropyl group in the formula (I) is a (1R,2S)-2-halogenocyclopropyl group;
the aforementioned compound, its salts and hydrates thereof, wherein the halogen atom of the halogenocyclopropyl group in the formula (I) is a fluorine atom;
the aforementioned compound, its salts and hydrates thereof, wherein the compound of formula (I) is a stereochemically pure compound;
the aforementioned compound, its salts and hydrates thereof, wherein n in the formula (I) is 1;
the aforementioned compound, its salts and hydrates thereof, wherein the compound of formula (I) is a stereochemically pure compound;
7-[3-[1-(S)-amino-1-cyclopropyl]methylpyrrolidin-1-yl]-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid, its salts and hydrates thereof; 5-amino-7-[3-[1-(S)-amino-1-cyclopropyl]methylpyrrolidin-1-yl]-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid, its salts and hydrates thereof;
5-amino-7-[3-[1-(S)-amino-1-cyclopropyl]methylpyrrolidin-1-yl]-6,8-difluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, its salts and hydrates thereof; the aforementioned compound, its salts and hydrates thereof, wherein Y is a hydrogen atom;
a drug containing the aforementioned compound, its salts and hydrates thereof as an active ingredient; and
an antibacterial agent containing the aforementioned compound, its salts and hydrates thereof as an active ingredient.
Each of the substituents of the compound of the present invention represented by formula (I): 
(wherein R1, R2, n and Q are as defined in the foregoing) will be explained in the following.
The substituents R1 and R2 is each independently a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, wherein the alkyl group may have one or more substituents selected from the group consisting of a hydroxyl group, a halogen atom, an alkylthio group having 1 to 6 carbon atoms and an alkyloxy group.
The alkyl group may be either straight or branched group having 1 to 6 carbon atoms, and the preferred examples thereof are methyl, ethyl, normal propyl and isopropyl groups.
When the alkyl group has a hydroxyl group as a substituent, the alkyl group may be either straight or branched form having 1 to 6 carbon atoms, and the hydroxyl group may preferably be substituted on the terminal carbon atom of the alkyl group. Preferred examples of the allyl group having a hydroxyl group include those which have 1 to 3 carbon atoms, such as a hydroxymethyl group, a 2-hydroxyethyl group, a 2-hydroxypropyl group and a 3-hydroxypropyl group.
When the alkyl group has a halogen atom as a substituent, the alkyl group may be either straight or branched form having 1 to 6 carbon atoms, and a fluorine atom is desirable as the halogen atom. With regard to the number of fluorine atoms, it may be any one of from mono-substitution to perfluoro substitution. The examples thereof are monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl and 2,2,2-trifluoroethyl groups. Among these groups, a monofluoromethyl group and a 2-fluoroethyl group are more preferred.
When the alkyl group has an alkylthio group as a substituent, the alkyl group may be either straight or branched form having 1 to 6 carbon atoms, and the alkylthio group may also be either straight or branched form having 1 to 6 carbon atoms. An alkylthiomethyl group, an alkylthioethyl group and an alkylthiopropyl group are desirable as the alkyl group having an alkylthio group, and the alkylthio group may preferably have 1 to 3 carbon atoms. More preferred examples are a methylthiomethyl group, an ethylthiomethyl group and a methylthioethyl group.
When the alkyl group has an alkoxyl group as a substituent, the alkyl group may be either straight or branched form having 1 to 6 carbon atoms, and the alkoxyl group may also be either straight or branched form having 1 to 6 carbon atoms. An alkoxymethyl group, an alkoxyethyl group and an alkoxypropyl group are desirable as the alkyl group having an alkoxyl group, and the alkoxyl group may preferably have up to 3 carbon atoms. More preferred examples thereof are a methoxymethyl group, an ethoxymethyl group and a methoxyethyl group.
The symbol n is an integer of from 1 to 4, preferably 1 or 2, and more preferably 1.
Q is a partial structure represented by the following formula (Ia). 
In the above formula (Ia), R3 is an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, a halogenoalkyl group having 1 to 6 carbon atoms, a cyclic alkyl group having 3 to 6 carbon atoms which may have a substituent, an aryl group which may have a substituent, a heteroaryl group which may have a substituent, an alkoxyl group having 1 to 6 carbon atoms or an alkylamino group having 1 to 6 carbon atoms.
In this case, an ethyl group is particularly desirable as the alkyl group having 1 to 6 carbon atoms. As the alkenyl group having 2 to 6 carbon atoms, a vinyl group or a 1-isopropenyl group is desirable. A 2-fluoroethyl group is desirable as the halogenoalkyl group having 1 to 6 carbon atoms. A cyclopropyl group is particularly desirable as the cyclic alkyl group, and a halogen atom, particularly a fluorine atom, is desirable as the substituent of the cyclic alkyl group.
Examples of the aryl group which may have a substituent are a phenyl group which may have 1 to 3 substituents selected from the group consisting for example of fluorine, chlorine, bromine or the like halogen atom, a hydroxyl group, an amino group, a nitro group, an alkyl group having 1 to 6 carbon atoms and an alkoxyl group having 1 to 6 carbon atoms, and its preferred illustrative examples are a phenyl group, a 2-fluorophenyl group, a 4-fluorophenyl group, a 2,4-difluorophenyl group, a 2-fluoro-4-hydroxyphenyl group, a 3-amino-4,6-difluorophenyl group and a 4,6-difluoro-3 methylaminophenyl group.
The heteroaryl group is a compound derived from a five or six-membered aromatic heterocyclic compound which contains one or more hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom. Examples thereof are a pyridyl group and a pyrimidyl group. As the substituent on these rings, an alkyl group, a halogen atom or the like is desirable. Particularly preferred is a 5-amino-2,4-difluoropyridyl group.
A methoxyl group is desirable as the alkoxyl group having 1 to 6 carbon atoms. A methylamino group is desirable as the alkylamino group having 1 to 6 carbon atoms.
As the substituent R3, a cyclic alkyl group or a halogenocycloalkyl group is desirable. Among these groups, a cyclopropyl group or a 2-halogenocyclopropyl group is particularly desirable. As the halogen atom, a fluorine atom is desirable.
The substituent R4 is a hydrogen atom or an alkylthio group having 1 to 6 carbon atoms, or R3 and R4 may together form a ring structure by incorporating a part of the mother skeleton (namely by including the nitrogen atom to which R3 is bonded and the carbon atom to which R4 is bonded). The thus formed ring may contain a sulfur atom as its constituting atom, and the ring may further have an alkyl group having 1 to 6 carbon atoms as a substituent. The ring to be formed herein may have a size of from four-membered ring to six-membered ring, and the ring may be saturated or unsaturated.
The substituent X1 is a halogen atom or a hydrogen atom, and a fluorine atom is desirable in the case of the halogen atom. Among these atoms, a fluorine atom or a hydrogen atom is desirable as the substituent.
The substituent R5 is a hydrogen atom, an amino group, a hydroxyl group, a thiol group, a halogenomethyl group, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms or an alkoxyl group having 1 to 6 carbon atoms, wherein the amino group may have one or two substituents selected from the group consisting of a formyl group, an alkyl group having 1 to 6 carbon atoms and an acyl group having 2 to 6 carbon atoms.
The alkyl group may be either straight or branched group having 1 to 6 carbon atoms, and its preferred examples are a methyl group, an ethyl group, a normal propyl group and an isopropyl group. The alkenyl group may be either straight or branched group having 2 to 6 carbon atoms and is preferably a vinyl group. The alkynyl group may be either straight or branched group having 2 to 6 carbon atoms and is preferably an ethynyl group. A fluorine atom is particularly desirable as the halogen of the halogenomethyl group, and its number may be from 1 to 3. The alkoxyl group may have 1 to 6 carbon atoms and is preferably a methoxyl group.
The substituent 5 is preferably a hydrogen atom, an alkyl group or an amino group, of which a methyl group or an unsubstituted amino group is more preferred.
When the substituent R5 is an amino group, a hydroxyl group or a thiol group, these groups may be protected with ordinally used protective groups.
Examples of such protective groups include tert-butoxycarbonyl, 2,2,2-trichloroethoxycarbonyl and the like alkoxycarbonyl groups, benzyloxycarbonyl, para-methoxybenzyloxycarbonyl, para-nitrobenzyloxycarbonyl and the like aralkyloxycarbonyl groups, acetyl, methoxyacetyl, trifluoroacetyl, chloroacetyl, pivaloyl, formyl, benzoyl and the like acyl groups, tert-butyl, benzyl, para-nitrobenzyl, para-methoxybenzyl, triphenylmethyl and the like alkyl or aralkyl groups, methoxymethyl, tert-butoxymethyl, tetrahydropyranyl, 2,2,2-trichloroethoxymethyl and the like ethers and trimethylsilyl, isopropyldimethylsilyl, tert-butyldimethylsilyl, tribenzylsilyl, tert-butyldiphenylsilyl and the like substituted silyl groups. Compounds whose substituents are protected with these protective groups are particularly useful as production intermediates.
When A1 is a partial structure represented by formula (II): 
X2 is a hydrogen atom, an amino group, a halogen atom, a cyano group, a halogenomethyl group, a halogenomethoxyl group, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms or an alkoxyl group having 1 to 6 carbon atoms, wherein the amino group may have one or two substituents selected from the group consisting of a formyl group, an alkyl group having 1 to 6 carbon atoms and an acyl group having 2 to 5 carbon atoms.
The alkyl group may be either straight or branched group having 1 to 6 carbon atoms and the preferred examples thereof are a methyl group, an ethyl group, a normal propyl group and an isopropyl group. The alkenyl group may be either straight or branched group having 2 to 6 carbon atoms and is preferably a vinyl group. The alkynyl group may be either straight or branched group having 2 to 6 carbon atoms and is preferably an ethynyl group. A fluorine atom is particularly desirable as the halogen of the halogenomethyl group, and its number may be from 1 to 3. The alkoxyl group may have 1 to 6 carbon atoms and is preferably methoxyl group. A fluorine atom is particularly desirable as the halogen of the halogenamethoxyl group, and its number may be from 1 to 3.
Among these substituents, a halogen atom, an alkyl group or an alkoxyl group is desirable, and a fluorine atom, a methyl group or a methoxyl group is more desirable. These substituents are particularly desirable in the case where Q is the partial structure represented by the formula (Ia).
In addition, X2 and the aforementioned R3 may together form a hydrocarbon ring structure (size of the ring may be from four-membered ring to seven-membered ring, and the ring may be saturated or unsaturated) by incorporating a part of the mother skeleton (namely by including the carbon atom to which X2 is bonded and the nitrogen atom to which R3 is bonded), and the thus formed ring may contain an oxygen atom, a nitrogen atom or a sulfur atom as its constituting atom, and the ring may also have an alkyl group having 1 to 6 carbon atoms as a substituent.
The partial structure represented by the aforementioned formula (Ia) is desirable as Q. In this case, it is desirable that A1 is the partial structure of formula (II).
When Q is the partial structure of formula (Ia) and A1 is the partial structure of the formula (II), a preferred combination of R5 and X2 is a case in which R5 is an amino group, a hydrogen atom, a hydroxyl group or an alkyl group having 1 to 6 carbon atoms and X2 is a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, a halogenomethoxyl group or a hydrogen atom.
A more preferred combination is a case in which R5 is an amino group, a hydrogen atom, a hydroxyl group or a methyl group and X2 is a fluorine atom, a methyl group, a methoxyl group, a difluoramethoxyl group or a hydrogen atom.
A most preferred combination is a case in which R5 is an amino group, a hydrogen atom, a hydroxyl group or a methyl group and X2 is a fluorine atom, a methyl group or a methoxyl group. For these R5 and X2 groups, a fluorine atom is desirable as X1.
When the substituents X1 and X2 are halogen atoms, X1 is particularly preferably a fluorine atom and X2 is preferably a fluorine atom or a chlorine atom.
Next, the halogenocyclopropyl group of R3 will be explained.
As the substitutable halogen atom, a fluorine atom and a chlorine atom can be exemplified, of which a fluorine atom is particularly preferred.
Regarding the steric environment at this moiety, it is particularly desirable that the halogen atom and pyridonecarboxylic acid moiety take cis-configuration on the cyclopropane ring.
So-called enantiomorphic isomers are present due to the cis-2-halogenocyclopropyl moiety alone of R3, and strong antibacterial activity and high safety have been found in both isomers.
The compound of the present invention shows excellent characteristics by having a substituent represented by the following formula at the 10-position of the 2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de][1.4]benzoxazine-6-carboxylic acid skeleton or at the 7-position of the 6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid skeleton. 
This substituent exists in the following four optical isomeric forms, due to the asymmetric carbon atom at 3-position of the pyrrolidine ring and the asymmetric carbon atom at 1-position of the cycloalkyl-substituted aminomethyl substituent. 
Among these, the present inventors considered that the structure of the following formula was more desirable. 
That is, it was revealed that, when the 10-position of the 2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de][1.4]benzoxazine-6-carboxylic acid skeleton or the 7-position of the 6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid skeleton has the substituent represented by the above formula, the compound of the present invention shows strong antibacterial activity upon Gram-negative bacteria and Gram-positive bacteria and also shows excellent safety and good pharmacokinetics, such as negativness of the micronuclear test (very weak micronucleus induction toxicity) which was not expected before the present invention.
Where the compound of formula (I) of the present invention has a structure allowing the existence of diastereomers, it is desirable to administer a compound comprising a pure diastereomer in administration to humans or animals. The term xe2x80x9ccomprising a pure diastereomerxe2x80x9d as used herein means not only a case in which it is completely free from the other diastereomer(s) but also a case in which it is in a chemically pure degree. In other words, it is interpretable that the other diastereomer(s) may be present in such a degree that it does not exert influences upon physical constants and physiological activities of the compound.
Also, the term xe2x80x9cstereochemically purexe2x80x9d as used herein means a compound consisting of one of its stereoiomers when the compound has a plurality of isomers due to asymmetric carbon atom (s) contained therein. The term xe2x80x9cpurexe2x80x9d in this case can also be considered in the same manner as described above.
The compound of the present invention may be used either in its free form or as an acid addition salt or a salt of its carboxyl group. Examples of the acid addition salt include hydrochloride, sulfate, nitrate, hydrobromide, hydroiodide, phosphate and the like inorganic acid salts, or methanesulfonate, benzenesulfonate, toluenesulfonate (sulfonate), acetate, citrate, maleate, fumarate, lactate (carboxylate) and the like organic acid salts.
The salt of carboxyl group may be either inorganic or organic salt, and its illustrative examples include lithium salt, sodium salt, potassium salt and the like alkali metal salts, magnesium salt, calcium salt and the like alkaline earth metal salts, ammonium salt, or triethylamine salt, N-methylglucamine salt, tris-(hydroxylmethyl)aminomethane salt and the like.
Also, these free form, acid addition salts and salts of carboxyl group of the compound may be present as hydrates.
When the compound of the present invention is used for antibacterial purpose, it is desirable to use a carboxylic acid compound in which the group Y is a hydrogen atom, while a quinolone derivative whose carboxylic acid moiety is an ester is useful as a synthesis intermediate or a prodrug. For example, alkyl esters, benzyl esters, alkoxyalkyl esters, phenylalkyl esters and phenyl esters are useful as synthesis intermediates.
Also, the ester to be used as a prodrug is an ester which is susceptible to an in vivo cleavage to form a free carboxylic acid, and its illustrative examples include acetoxymethyl ester, pivaloyloxymethyl ester, ethoxycarbonyl ester, choline ester, dimethylaminoethyl ester, 5-indanyl ester, phthalidinyl ester, 5-alkyl-2-oxo-1,3-dioxol-4-ylmethyl ester, and oxoalkyl ester such as 3-acetoxy-2-oxobutyl eater.
The compound of the present invention represented by the formula (I) can be produced by various method, and, in a preferred example of these methods, it can be produced for example by reacting a compound represented by formula (III): 
[wherein X3 is a substituent which functions as a leaving group, such as a fluorine atom, a chlorine atom, a bromine atom, a substituted or unsubstituted phenylsulfonyl group or a substituted or unsubstituted alkylsulfonyl group having 1 to 3 carbon atoms,
Y1 is the Y defined in the formula (I) or a boron-containing group represented by formula (IV):
xe2x80x94B(Y11)Y12xe2x80x83xe2x80x83(IV)
(wherein Y11 and Y12 each represents a fluorine atom or an alkylcarbonyloxy group having 2 to 4 carbon atoms), and R3, R4, R5, A1 and X1 are as defined in the formula (I)] with a compound represented by formula (V): 
[wherein R11 and R21 each independently represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or a protective group for amino group, in which the alkyl group may have a substituent selected from the group consisting of a hydroxyl group, a halogen atom, an alkylthio group having 1 to 6 carbon atoms and an alkoxyl group having 1 to 6 carbon atoms, and n is as defined in the formula (I)] or an addition salt thereof (examples of the acid addition salt include hydrochloride, sulfate, nitrate, hydrobromide, hydroiodide, phosphate and the like inorganic acid salts, or methanesulfonate, benzenesulfonate, toluenesulfonate (sulfonate), acetate, citrate, maleate, fumarate, lactate (carboxylate) and the like organic acid salts).
The reaction can be carried out using or without using a solvent. The solvent to be used in the reaction may be any solvent which is inert under the reaction conditions, and its illustrative examples include dimethyl sulfoxide, pyridine, acetonitrile, ethanol, chloroform, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, water and 3-methoxybutanol or a mixture thereof.
Preferably, the reaction may be carried out in the presence of an acid acceptor such as an inorganic base (e.g., an alkali metal or alkaline earth metal carbonate or bicarbonate) or an organic base (e.g., triethylamine, pyridine, 1,8-diazabicycloundecene).
The reaction can be carried out at a temperature of from room temperature to 200xc2x0 C., preferably from 25 to 150xc2x0 C. The reaction is carried out for a period of from 30 minutes to 48 hours and completes generally after about 30 minutes to 2 hours.
When the amino group is protected, examples of the protective group for amino group include those which are generally used in this field, such as tert-butoxycarbonyl, 2,2,2-trichloroethoxycarbonyl and the like alkoxycarbonyl groups, benzyloxycarbonyl, para-methoxybenzyloxycarbonyl, para-nitrobenzyloxycarbonyl and the like aralkyloxycarbonyl groups, acetyl, methoxyacetyl, trifluoroacetyl, chloroacetyl, pivaloyl, formyl, benzoyl and the like acyl groups, tert-butyl, benzyl, para-nitrobenzyl, para-methoxybenzyl, triphenylmethyl and the like alkyl or aralkyl groups, methoxymethyl, tert-butoxymethyl, tetrahydropyranyl, 2,2,2-trichloroethoxymethyl and the like ethers and trimethylsilyl, isopropyldimethylsilyl, tert-butyldimethylsilyl, tribenzylsilyl, tert-butyldiphenylsilyl and the like substituted silyl groups.
When Y and Y1 are an alkyl group having 1 to 6 carbon atoms, an alkoxymethyl group having 2 to 7 carbon atoms or a phenylalkyl group composed of an alkylene group having 1 to 6 carbon atoms and phenyl group, the compound of interest can be converted into its corresponding carboxylic acid compound by treating it under an acidic or basic condition which is generally employed for the hydrolysis of carboxylic acid esters.
When Y1 is a structure of the formula (IV), its conversion into corresponding carboxylic acid compound can be effected by allowing the compound (III) to react with the compound (V) and then treating it under an acidic or basic condition.
In addition, when de-protection is necessary, the compound of interest represented by the formula (I) can be obtained by removing the protective group under suitable conditions for the protective group.
The compound of formula (V) can be produced by various methods, and, though not particularly limited, it can be synthesized by a method shown in the reference examples as a preferred example in which synthesis of 3-[1-(S)-amino-1-cycloalkyl]methylpyrrolidine is described as a synthetic example of 3-[1-amino-1-cycloalkyl]methylpyrrolidine, so that the compound of formula (V) can be produced in accordance with this method using a known optically active cycloalkyl-substituted glycine derivative.
The cis-2-fluorocyclopropylamine comprised of a pure isomer, which is desirable for the synthesis of the compound of formula (I) comprised of a pure isomer, can be synthesized for example by the method described in JP-A-2-231475 (the term xe2x80x9cJP-Axe2x80x9d as used herein means an xe2x80x9cunexamined published Japanese patent applicationxe2x80x9d). Synthesis of the compound of formula (I) comprised of a pure isomer can be carried out using the thus obtained optically active cis-2-fluorocyclopropylamine derivative as the material, in accordance with the method described for example in JP-A-2-231475.
The following can be cited as illustrative examples of the compound of the present invention.
10-[3-(R)-[1-(S)-Amino-1-cyclopropyl]methylpyrrolidine-1-yl]-9-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de][1.4]benzoxazine-6-carboxylic acid;
8-amino-10-[3-(R)-[1-(S)-amino-1-cyclopropyl]methylpyrrolidine-1-yl]-9-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de][1.4]benzoxazine-6-carboxylic acid;
7-[3-(R)-[1-(S)-amino-1-cyclopropyl]methylpyrrolidin-1-yl]-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8methoxy-4-oxoquinoline-3-carboxylic acid;
5-amino-7-[3-(R)-[1-(S)-amino-1-cyclopropyl]methylpyrrolidin-1-yl]6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid;
7-[3-(R)-[1-(S)-amino-1-cyclopropyl]methylpyrrolidin-1-yl]-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid;
5-amino-7-[3-(R)-[1-(S)-amino-1-cyclopropyl]methylpyrrolidin-1-yl]-6,8-difluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid; and
5-amino-7-[3-(R)-[1-(S)-cyclopropyl-1-N-methylamino]methylpyrrolidin-1-yl]-6,8-difluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.
These compounds have the following structures. 
Since the compound of the present invention has strong antibacterial actions, it can be used as drugs for use in human bodies, animals and fishes or as preservatives of agricultural chemicals and food.
When the compound of the present invention is used as a drug for human bodies, its dose is within the range of from 50 mg to 1 g, preferably from 100 mg to 300 mg, per day for an adult.
Its dose as a drug for use in animals varies depending on the purpose of its administration (treatment or prevention), kind and size of each animal to be treated and kind and degree of each infected pathogenic bacterium, but the dose may be within the range of generally from 1 mg to 200 mg, preferably from 5 mg to 100 mg, per 1 kg body weight per day.
The daily dose may be used once a day or by dividing it into 2 to 4 doses per day. As occasion demands, the daily dose may exceed the aforementioned range.
Since the compound of the present invention is active against a broad range of microorganisms causing various infectious diseases and effective to treat, prevent or alleviate diseases induced by these pathogens.
Illustrative examples of bacteria and bacterioid microorganisms on which the compound of the present invention is effective include those which belong to the genus Staphylococcus, Streptococcus pyogens, hemolytic streptococci, enterococcus, pneumococcus, those which belong to the genus Peptostreptococcus, Neisseria gonorrhoeae, Escherichia coli, those which belong to the genera Citrobacter and Shigella, Klebsiella pneumoniae, those which belong to the genera Enterobacter, Serratia and Proteus, Pseudomonas aeruginosa, Haemophilus influenzae, those which belong to the genera Acinetobacter and Campylobacter and Chlamydia trachomatis. Illustrative examples of diseases which are induced by these pathogens include folliculitis, furuncle, carbuncle, erysipelas, phlegmon, lymphangitis/lymphadenitis, felon, subcutaneous abscess, hidradenitis, acne conglobata, infectious atheroma, perirectal abscess, mastitis, superficial secondary infections after injury, burn injury, operative wound and the like, pharyngitis, acute bronchitis, tonsilitis, chronic bronchitis, bronchiectasis, diffuse bronchiolitis, secondary infection of chronic respiratory disease, pneumonia, pyelonephritis, cystitis, prostatitis, epididymitis, gonococcal urethritis, nonspecific urethritis, cholecystitis, cholangitis, bacillary dysentery, enteritis, uterine adnexitis, intrauterine infection, bartholinitis, blepharitis, hordeolum, dacryocystitis, tarsadenitis, corneal ulcer, octitis media, sinusitis, periodentitis, pericoronitis, jaw infection, peritonitis, endocarditis, sepsis, meningitis and skin infection.
The compound of the present invention is also effective against various microorganisms causing infectious diseases in animals, such as those which belong to the genera Escherichia, Salmonella, Pasteurella, Haemaphilus, Bordetella, Staphylococcus and Mycoplasma. Illustrative examples of such diseases include colibacillosis, pullorum disease, avian paratyphoid, avian cholera, infectious coryza, staphylococcosis, mycoplasma infection and the like in the case of birds; colibacillosis, salmonellosis, pasteurellosis, haemophilus infection, atrophic rhinitis, exudative epidermis, mycoplasma infection and the like in the case of pigs; colibacillosis, salmonellosis, hemorrhagic sepsis, mycoplasma infection, bovine pleuropneumonia, bovine mastitis and the like in the case of cattle; colisepsis, salmonella infection, hemorrhagic sepsis, uterine empyema, cystitis and the like in the case of dogs; and exudative pleurisy, cystitis, chronic rhinitis, haemophilus infection, kitten diarrhea, mycoplasma infection and the like in the case of cats.
The antibacterial preparation which comprises the compound of the present invention can be prepared by selecting an appropriate preparation depending on each administration method and employing generally used various preparation method. Regarding the dosage form of the antibacterial preparation which uses the compound of the present invention as its principal agent, tablets, powders, granules, capsules, solutions, syrups, elixirs, oily or aqueous suspensions and the like can be exemplified as oral preparations.
Regarding injections, a stabilizing agent, an antiseptic agent and a solubilizing agent may be used in the preparation, or a solution which may contain these auxiliary agents may be contained in a container and made into a solid preparation by freeze-drying or the like means to be re-dissolved when used. In addition, a single dose may be contained in a single container or multiple doses may be contained in the same container.
Also, solutions, suspensions, emulsions, ointments, gels, creams, lotions, sprays and the like can be exemplified as preparations for external use.
Solid preparations may contain pharmaceutically acceptable additives together with the active compound and can be prepared for example by mixing the compound with additives optionally selected from fillers, extenders, binders, disintegrators, solubilization enhancing agents, moistening agents, lubricating agents and the like. As liquid preparations, solutions, suspensions, emulsions and the like can be exemplified, which may contain a suspending agent, an emulsifying agent and the like as additives.
Examples of the method for administering the compound of the present invention to animals include a method in which it is orally administered directly or by mixing it with feed, a method in which it is made into a solution and then orally administered directly or by mixing it with drinking water or feed and a method in which it is administered by injection.
Regarding the pharmaceutical preparations for use in the administration of the compound of the present invention to animals, it can be made optionally into powders, fine subtilaes, soluble powders, syrups, solutions or injections making use of the techniques generally used in this field.
Formulation examples of the pharmaceutical preparations are shown below.